THE IMPRINTED BRAIN THEORY

According to the so-called imprinted brain theory, the paradoxes can be explained in terms of the expression of genes, and not simply their inheritance. Imprinted genes are those which are only expressed when they are inherited from one parent rather than the other. The classic example is IGF2, a growth factor gene only normally expressed when inherited from the father, but silent when inherited from the mother. According to the most widely-accepted theory, genes like IGF2 are silenced by mammalian mothers because only the mother has to pay the costs associated with gestating and giving birth to a large offspring. The father, on the other hand, gets all the benefit of larger offspring, but pays none of the costs. Therefore his copy is activated. The symbolism of a tug-of-war represents the mother's genetic self-interest in countering the growth-enhancing demands of the father's genes expressed in the foetus—the mother, after all, has to gestate and give birth to the baby at enormous cost to herself.

Edge wrote to Badcock, an early member of the Edge community, to ask him for a summary of his new theory for our readers.

"At first sight," he wrote back in an email, "it would seem that no single theory could explain these seemingly contradictory facts—and certainly not an evolutionary or genetic one—but an attempt is underway to do exactly that which has just passed its first major test. In 2006 Bernard Crespi (Killam Research Professor in the Department of Biosciences, Simon Fraser University) and I published a paper in The Journal of Evolutionary Biology setting out the theory in relation to autism. Earlier this year Behavioral and Brain Sciences published a second paper along with 23 expert commentaries and the authors' replies which extends the idea to psychoses like schizophrenia. More recently still, Nature has published our essay on the theory ("Battle of Sexes May Set The Brain", 28 August 2008)."

What causes mental illnesses like schizophrenia and autism? We have long known that both tend to run in families and that if one of two identical twins has such a disorder, there is a much higher than average probability that the other will too. Autism is sometimes associated with genetic syndromes, such as Rett, Down, and Turner's, Phenylketonuria, and Tuberous Sclerosis. The clearest single-gene cause of autism spectrum disorder (ASD) is Fragile X syndrome, with a wide range of severity in symptoms and 25-47 per cent of affected males meeting the criteria for autism. But neither autism nor schizophrenia obeys classical Mendelian laws of inheritance in the way that Cystic Fibrosis or some types of colour blindness do.

However, there is also good evidence for social, environmental causes of mental illnesses. Studies of the Dutch wartime famine and of the Chinese famine of 1959–61 reported increased incidence of schizophrenia among children born just after the events. And a study of 2 million Swedish children born between 1963 and 1983 revealed a significant link between schizophrenia and poverty in childhood. Those with 4 out of 5 measured indicators of hardship had an almost 3-fold greater risk of schizophrenia than those with none. Where ASD is concerned, the exponential increase in diagnoses since the 1980s has prompted some to suggest environmental or social causes: most controversially, childhood vaccines like MMR. Autism can certainly result from ethanol or valproic acid poisoning during the mother's pregnancy, and in the 1964 rubella epidemic in the USA, the rate of incidence of autism exceeded 7 per cent at a time when the normal rate of diagnosis was not much more than a tenth of one per cent. ASD can also be caused by thalidomide, where it affects about 5 per cent of those with birth defects attributable to this cause.

The figure illustrates the idea. According to the so-called imprinted brain theory, the paradoxes can be explained in terms of the expression of genes, and not simply their inheritance. Imprinted genes are those which are only expressed when they are inherited from one parent rather than the other. The classic example is IGF2, a growth factor gene only normally expressed when inherited from the father, but silent when inherited from the mother. According to the most widely-accepted theory, genes like IGF2 are silenced by mammalian mothers because only the mother has to pay the costs associated with gestating and giving birth to a large offspring. The father, on the other hand, gets all the benefit of larger offspring, but pays none of the costs. Therefore his copy is activated. The symbolism of a tug-of-war represents the mother's genetic self-interest in countering the growth-enhancing demands of the father's genes expressed in the foetus—the mother, after all, has to gestate and give birth to the baby at enormous cost to herself.

Mental disorders can be located along a dimension of mentalism (aka 'theory-ofmind,' 'folk-psychology' or 'people skills') defined as our evolved ability to comprehend others' actions and behaviour in purely mental terms (such as intention, belief, desire, emotion etc.). Autistics, notoriously, are poor where mentalistic skills like inferring intention or understanding false belief are concerned. ASDs therefore belong on the hypo-mentalistic side of the continuum. However, what we would now term psychotic spectrum disorders (PSDs) can be typified as hyper-mentalistic: paranoid schizophrenics, for example, symptomatically over-interpret intention either positively in erotomania (delusions that others are in love with you) or negatively in delusions of persecution. They also entertain bizarre false beliefs about themselves and others, and generally exhibit excessive mentalism, often enshrined in quasi-religious or mystical delusions. Indeed, the symptoms and signs of autism and psychoses like paranoid schizophrenia exhibit a remarkable pattern of antithesis:

Autism/Asperger's syndrome

Psychosis/Paranoid schizophrenia

gaze-monitoring deficits

delusions of being watched/spied on

apparent deafness/insensitivity to voices

hallucination of and hyper-sensitivity to voices

deficits in interpreting others' intentions

erotomania/delusions of persecution

deficits in appreciating shared-attention/groups

delusions of conspiracy

theory of mind deficits

magical ideation/delusions of reference

deficit in sense of personal agency/episodic memory

megalomania/delusions of grandeur

literalness/inability to deceive

delusional self-deception

pathological single-mindedness

pathological ambivalence

early onset

late onset

The concepts of hypo- and hyper-mentalism readily explain the last item: age of onset. Typically, this is early childhood for autism but late adolescence or adulthood for schizophrenia: a difference which up until now has lacked an obvious explanation. But the fact that you have to develop normal mentalistic skills before you can over-develop them to the point of psychosis readily explains why the mentalistic deficits of autism are apparent in childhood and why the hyper-mentalism of psychosis can only become fully apparent much later. Mentalism appears to be the key to social behaviour because autistics are notably non-social in the sense that they typically lack social skills and have impoverished social lives with few if any friends, little interest in group activities, and muted emotional responses such as empathy and interest in others. Consequently their behaviour often seems callous, childish, or self-centred. However, mammals as a whole show a notable sex-difference in social behaviour to which human beings are no exception. In general, females have been found to be more sociable, co-operative, and nurturing than males — particularly among primates. This may explain why the mother's genes appear to promote mentalism in human beings and why the father's seem to motivate more self-interested behaviour. From an evolutionary point of view, every one of a mother's offspring carries an equal complement of her genes (half of them). But uncertainty of paternity—the bane of mammals thanks to internal, unseen fertilization—means that the genes of a father have no necessary reason to find themselves in any of a woman's other children: Mother's baby. Father's? Maybe! The result is that, from an evolutionary and genetic point of view, paternallyactive genes do not have the same self-interest in family cohesion and social cooperation that the mother's characteristically do. Why should the father's encourage his offspring to co-operate with those of the mother's other mates?

Nevertheless, paternal genes do have a more positive cognitive bias of their own: what you might call mechanistic cognition. This is the mode of cognition that we have evolved to interact with the physical, non-human, natural environment, and stands in contrast to mentalistic cognition, which evolved to facilitate social contact and cognition in relation to other people. Significantly, autistics often show compensations for their mentalistic deficits in mechanistic cognitive skills, one of the most common being calendar calculation (such as knowing the date of Easter in any year you care to name), rote memorization, and maths skills. Indeed, the attraction of like-minded people with mechanistic cognitive configurations is probably part of the explanation for the remarkably high incidence of ASD in Silicon Valley, California, and in the Cambridge area in the UK—both places with high levels of employment in maths-, computer- and science-based industries.

If we have evolved two parallel cognitive systems rather than just one, they appear to vary in the same way that vulnerability to ASD or PSD does: more paternal influence predisposes to mentalistic deficits, but mechanistic compensations; and more maternal influence is the converse. A counter-intuitive prediction of this model corroborated by some recent clinical findings is that hyper-mentalism should go with mechanistic deficits in exactly the same way that autistic hypo-mentalism goes with mentalistic deficits. Indeed, this model also suggests that if there are autistic savants with outstanding skills in mechanistic aspects of cognition, there ought also to be psychotic ones with the opposite, mentalistic ones. However, the very same excellence in mentalism would make such psychotic savants much less noticeable than their autistic counterparts, whose deficits immediately identify them as odd, socially-isolated, and eccentric. Psychotic savants, by contrast, can be expected to be deeply embedded in successful social networks, and found at the centre of excellence in such things as religious and ideological evangelism; literary and theatrical culture; litigation and the law; hypnosis, faith-healing, and psychotherapy; fashion and advertising; politics, public-relations and the media; commerce, confidence-trickery, and fraud of all kinds. The following table gives some idea of the inverted symmetry to be found between mentalistic and mechanistic cognition:

Mentalistic Cognition

Mechanistic Cognition

psychological interaction with self and others

physical interaction with nature and objects

uses social, psychological, and political skills

uses mechanical, spatial, and engineering skills

deficits in autism, augmented in women

accentuated in autism, augmented in men

voluntaristic, subjective, particularistic

deterministic, objective, universal

abstract, general, ambivalent

concrete, specific, single-minded

verbal, metaphoric, conformist

visual, literal, eccentric

top-down, holistic, centrally-coherent

bottom-up, reductionistic, field-independent

epitomized in literature, politics, and religion

epitomized in science, engineering, and technology

‘pseudo-science': astrology, alchemy, creationism

‘hard science': astronomy, chemistry, Darwinism

nurtured: culturally- and personally-determined

natural: factually- and genetically-determined

belief-based therapies: placebos, faith-healing, psychotherapy etc.

physical effect-based therapies: drugs, surgery, physiotherapy, etc.

According to this way of looking at things, development can be pushed to either extreme by any factors that affect gene expression either before or after birth. Valproic acid is known to do this, as is thalidomide and other environmental causes of autism. Where purely genetic factors are concerned, the theory proposes that increased expression of paternal genes like IGF2 will predispose to autism—and expression of that gene is now known to be enhanced in individuals with ASD. This will result in the features listed in the figure: higher birth weight, an increased vulnerability to cancer (which is another expression of over-growth), and a larger brain in childhood with more white matter. Furthermore, increased nutrition would mimic the effect of genes like IGF2 and predispose to growth, perhaps explaining part of the recent exponential increase in milder ASDs such as Asperger's syndrome. Indeed, the fact that birth-weights of new-born babies in Vienna rose an unprecedented amount during the 1920s perhaps partly explains why Asperger was to discover the autistic syndrome named after him during the next couple of decades. And because all fathers are male the new theory can also be reconciled with the extreme male brain theory of autism, which persuasively argues that ASDs can often be linked to increased testosterone exposure in utero and to the more lateralized brain characteristic of males.

Significantly then, PSD—and schizophrenia in particular—are associated with the features listed on the other side of the diagram: low birth weight, a reduced vulnerability to cancer (despite schizophrenics smoking much more!), and smaller adult brains with less white matter. Correspondingly, just as increased nutrition in pregnancy and/or early life might mimic paternally-active genes like IGF2 to predispose to ASD, the contrary conditions—starvation during pregnancy and/or early life—could be predicted to increase the risk of PSD, as we saw they indeed do, at least in the case of schizophrenia. And because all mothers are female, enhanced expression of maternal genes also goes with reduced foetal testosterone and the less lateralized brain typical of women. Indeed, the fact that mammalian females have two X sex chromosomes (XX) by contrast to the male's one (XY) means that X chromosome gene expression is also implicated. In cases where an extra X chromosome is present: X trisomy (XXX) and Klinefelter syndrome (XXY), the presence of the additional X results in brain features similar to those found in schizophrenia, along with a notably increased vulnerability to psychosis, just as the theory would predict.

Another controversial and counter-intuitive prediction of the theory for which there is already much evidence is that, if ASD has increased in modern societies with higher standards of living as it so spectacularly has done, then PSD should be falling. Interestingly in this respect, rates of admission for PSDs like schizophrenia have decreased by between 10 and 57 per cent in England and Wales, Scotland, Denmark, Australia, and New Zealand. Indeed, even Bleuler, who coined the term schizophrenia, noticed a secular decline in his own lifetime, and a recent Canadian study showed a 42 per cent decrease in the number of first-admission schizophrenia cases over 20 years. It found that annual inpatient prevalence rates decreased by 52 per cent between1986 and 1996, with no corresponding change in outpatient rates, regardless of sex. Although total major affective disorders increased, this was due to an increase in major depression, not bipolar disorder, which is now thought to be much more closely allied to schizophrenia than was once believed.

Surprisingly as it may seem, the new theory can even encompass the finding that infectious agents can sometimes be implicated in causing schizophrenia. People infected with the protozoan parasite Toxoplasma gondii are three times more likely to suffer from schizophrenia than those not infected, and so too are catowners. The significance of the latter may lie in the fact that the parasite can only complete the reproductive phase of its life-cycle inside a cat. It achieves this by causing its principal carriers, rats and mice, to lose their fear of cats, and so be much more likely to be eaten by one. Inside the rodent's brain, the parasite attacks the amygdalas, which play the same role in triggering fear-reactions that it does in humans. But when infected rats are treated with anti-psychotic drugs like those given to human schizophrenics the rats' fear of felines returns. Men with Toxoplasma infection tend to be more reckless than normal, and infected people of both sexes are almost three times more likely to be involved in car accidents, and have measurably slowed reaction times. In mice, only paternal genes are expressed in the amygdalas and there is good evidence suggesting that the same is true in humans. This finding suggests the intriguing possibility that an explanation may lie in the parasite suppressing paternally-controlled brain systems like the amygdala to produce an overall preponderance of maternal brain function, which according to the new theory is the fundamental basis of psychosis in general and of schizophrenia in particular. T. gondii, in other words, could be another of those environmental effects portrayed in black in the figure, but one pushing development pathologically towards the psychotic end of the spectrum by sabotaging brain systems built by paternal genes.

Finally, what of normal development? The implication is clear: so-called normality represents a more-or-less balanced expression of genes and environmental developmental influences. However, the fact that all fathers are male and all mothers are female implies that the norms for the sexes are likely to be slightly offset. This would fit with the finding that ASD afflicts more males than females and that men typically do worse on tests of mentalistic competence than do women. Women, on the other hand, would be symmetrically offset to the more mentalistic side of the spectrum, and this might explain why rates of incidence of schizophrenia among family members of women with the disorder are higher than those among family members of men with schizophrenia. And although there is a slightly higher incidence of schizophrenia overall in men, erotomania appears to be a predominantly female pathology, with women suffering more paranoid delusions and hallucinations than men, particularly in late-onset cases.

The model appears to rule out anyone suffering from an ASD and a PSD simultaneously, and such co-morbidity does appear to be rare—but is not unknown. However, I know of cases of individuals diagnosed with bipolar disorder who also show unmistakable signs of ASD during their non-manic phases. Indeed, I have research on one individual who suffers from severe gaze-aversion, autistic deficits in a sense of self and social anxiety most of the time, but who becomes comfortable with other people during manic episodes when his sense of self hypertrophies into megalomania with the feeling that he is the returned Jesus Christ! Furthermore, there is evidence of both ASD and PSD in Newton and Beethoven, and incontrovertibly so in the Nobel-prize winning mathematician John Nash. Here the theory predicts that the ASD must come first (typically in childhood) and leave a permanent savant-like basis later built on by hyper-mentalistic tendencies to produce an unusually broadened and dynamically-balanced cognitive configuration: that of true genius.

Such a far-reaching theory as this can be expected to be controversial, and much remains to be done to work out its detailed implications. But the theory does have one outstanding merit: it makes clear and profoundly counter-intuitive predictions about which genes are involved, about how they should be expressed, and about what effects they should be found to have in the brain and on behaviour. Twenty-three experts are only the start: Nature's comment will be decisive and, thanks to rapid progress in genomics and neuroscience, should not be long in coming.